A number of cytokines were discovered as protein factors which inhibit the expression of human physiological activities such as immune response, inflammation, hematopoiesis and the like, and their structures and functions have gradually been made clear. As a result, it is being clarified that the cytokines affect not only human immunological system but also various other human physiological activities and further have a close connection with the development, differentiation, homeostatis and diseases of human body.
Many cytokines such as TNF-α, IL-1β, IL-6, IFN-γ and the like are identified. It is known that they also have various pharmacological activities.
Of the above cytokines, TNF-α (Tumor necrosis factor-α) was discovered as an antineoplastic cytokine and was expected to be used as an anticancer agent. However, TNF-α was later found to be the same substance as cachectin (a cachexia inducer) and is reported to have, for example, a stimulating activity for production of IL-1 and other cytokines, an activity of proliferation of fibroblast, an endotoxin shock-inducing activity, an activity for increasing ICAM-1, ICAM-2 (intercellular adhesion molecules), ELAM (endothelial leukocyte adhesion molecule-1), etc. (these molecules are proteins for adhering leukocytes to endothelial cells) to accelerate the adhesion of leukocytes to endothelial cells, and an arthritis-causing activity such as bone resorption, cartilage destruction or the like [Beutler, B., et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989); Akatu, K. & Suda, T., Medical Practice, 8 (9) 1393-1396 (1991)].
It is also reported that the concentration of TNF in blood or neurolymph increases in infectious diseases by bacteria or parasites [Mitsuyama, M., Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), 159 (8) 467-470 (1991); Nakao, M., Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), 159 (8) 471-474 (1991)].
It is also reported that the activity of TNF is found in synovial fluid or serum, in chronic rheumatoid arthritis and that the activity is a TNF-α activity [Saxne, T., et al., Arthritis Rheum., 31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 (1991); Macnaul, K. L., et al., J. Immunol., 4154-4166 (1990); Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); Brennan, F. M., et al., Bri. J. Rheum., 31, 293-298 (1992)].
It is also reported that the concentration of TNF is high in the sputa of patients of ARDS (acute respiratory distress syndrome) which is a serious respiratory disease [Millar, A. B., et al., Nature, 322, 73 (1986)] and that TNF is associated with viral fulminant hepatitis [Muto, Y., et al., Lancet, ii, 72-74 (1986)].
It is also reported that the concentration of TNF-α in blood is high in myocardial ischemia such as acute myocardial infarction [Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)]. It is suggested that TNF-α is associated with such a disease [Lefer, A. M., et al., Science, 249, 61-64 (1990)]. It has recently been reported that TNF-α suppresses myocardial contractility [Finkel, M. S., et al., Science, 257, 387-389 (1992); Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)].
Currently, no satisfactory chemotherapy is developed yet for the above-mentioned various diseases such as chronic rheumatoid arthritis, endotoxin shock, ARDS and the like. To these diseases are merely applied, in a symptomatic treatment, steroidal agents, anti-inflammatory agents, agents for inhibition of platelet agglutination, antibiotics, etc. As it was suggested as mentioned above that there is a close connection between the above diseases and the rise in concentration or activity of TNF-α, it has recently been tried to apply TNF-α antibody or the like to the diseases; however, such an approach has given no satisfactory result, either. Therefore, it is desired in the art to develop a drug for treatment of the above diseases, which can suppress the excessive production of, in particular, TNF-α, according to a novel mechanism.
B cells are activated by antigen, proliferated and differentiated into antibody-producing cells. IL-6 is known to be a cytokine participating in this differentiation.
It is clear that IL-6 not only plays an important role in antibody production of B cells, but also induces the proliferation and differentiation of T cells. It is also clear that IL-6 acts on liver cells to induce the synthesis of proteins in acute phase, acts on hemopoietic cells to promote the formation of pluripotential colonies, and is an important factor in biophylactic systems such as immune system, hemopoietic system, nerve system, liver and the like.
As the diseases with which IL-6 is associated, there are mentioned a series of autoimmune diseases such as hyper-γ-globulinemia, chronic rheumatoid arthritis, systemic lupus erythematosus (SLE) and the like; monoclonal B cell abnormal disease (e.g. myeloma); polyclonal B cell abnormal disease; atrial myxoma; Castleman syndrome; primary glomerulonephritis; mesangial proliferative nephritis; cancerous cachexia; Lennander's lymphoma; psoriasis; Kaposi's sarcoma appearing in AIDS; postmenopausal osteoporosis; and so forth.
IL-1β is known to have various physiological activities. Specific examples of these activities are inhibition of tumor cell, increase of cytokine production from activated T cells, proliferation of fibroblast, synoviocyte and vessel endothelium, catabolism and thermacogenesis of cell, differentiation of activated B cell, increase of NK activity, adhesion of neutrophils, anti-inflammation, inhibition of radiation disorder, etc.
When IL-1β is produced at an increased rate and becomes excessive, IL-1β is thought to give rise to various diseases such as chronic rheumatoid arthritis, chronic inflammatory diseases and the like.
IFN is known to have various physiological activities and is actually detected in tissues and blood during many diseases. The diseases whose onset is considered to have a close connection with IFN, include viral infectious diseases, infectious diseases by microorganisms other than viruses, chronic rheumatoid arthritis, collagen diseases (e.g. SLE), I-type allergy, uveitis, Behcet's disease, sarcoidosis, arteriosclerosis, diabetes, fulminant hepatitis, malignant tumor, Kawasaki disease, wounds of skin or mucosa, etc. [Journal of clinical and Experimental Medicine (IGAKU NO AYUMI), 174 (14), p. 1077, 1995].
Neutrophils express a bactericidal action to the enemy incoming into human body, by migration, phagocytosis, production of reactive oxygen and release of lysosomal enzymes. However, neutrophils are known to adhere to vascular endothelial cells and further infiltrate into tissues during the ischemia or reperfusion, or acute inflammation of various tissues, leading to tissue disorder.
As stated above, various cytokines are known to cause various diseases when the cytokines become excessive owing to, for example, the abnormally high production thereof. Therefore, it is desired to ameliorate the abnormal state of cytokine to prevent or treat various diseases.
It is also desired to develop an agent for inhibiting the tissue disorder caused by adhesion of neutrophils to vascular endothelial cells.
Some of the thiazole derivatives represented by the following general formula (1):
(wherein R1 is a phenyl group which may have a lower alkoxy group(s) as a substituent(s) on the phenyl ring; and R2 is a group represented by the following general formula:
[wherein R3's, which may be the same or different, are each a carboxyl group, a lower alkoxy group, a lower alkyl group, a lower alkenyl group, a group represented by -(A)l-NR4R5 (A is a lower alkylene group; R4 and R5, which may be the same or different, are each a hydrogen atom or a lower alkyl group; and l is 0 or 1), a hydroxyl group-substituted lower alkyl group, a lower alkoxy group-substituted lower alkoxy group, a lower alkoxy group-substituted lower alkoxycarbonyl group or a carboxyl group-substituted lower alkoxy group; and m is an integer of 1-3], or a heterocyclic ring residue having 1-2 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which heterocyclic ring residue may have, as a substituent(s) on the heterocyclic ring, 1-3 groups selected from the group consisting of carboxyl group and lower alkoxy group) and salts thereof, are known in, for example, JP-A-5-51318 and JP-A-6-65222. These thiazole derivatives and salts thereof are also well-known to be useful as a reactive oxygen inhibitor.